Autophagy is a natural, conserved, process that allows the orderly degradation of cytoplasmic contents. There are three pathways of autophagy, macroautophagy, microautophagy and chaperone-mediated autophagy, of which macroautophagy is the main pathway. Autophagy plays several roles in cellular functioning including the breakdown and recycling of proteins, the degradation of infectious particles and the removal of damaged organelles, cell membranes and proteins. In certain diseases, called proteinopathies, accumulation of structurally abnormal proteins disrupts normal cellular function. There is a wide range of proteinopathies including many neurodegenerative disorders such as Parkinson's disease, Alzheimer's disease and amyotrophic lateral sclerosis. Strategies aimed at limiting the accumulation of the abnormal proteins, such as enhancing the removal of abnormal proteins, are being investigated as potential therapies for proteinopathies including neurodegenerative disorders. For reviews on autophagy and neurodegenerative disorders see Rubinsztein et al, J Exp Med., 2015, 212, pp. 979-990; Kiriyama and Nochi, Int J Mol Sci., 2015, 16, pp. 26797-26812.
Trehalose is a disaccharide that represents one such strategy to reduce the accumulation of abnormal proteins. The exact mechanism of action of trehalose is not known, however, it possesses several properties that may be useful in preventing neurodegeneration including stabilizing proteins, acting as a chemical chaperone for misfolded proteins and improving the clearance of abnormal proteins (for a review see Emanuele, Curr Drug Targets, 2014, 15, pp 551-557). Trehalose reduces levels of α-synuclein (αSYN), the protein which is misfolded in PD and drives the pathophysiology of the disease (for review see Wang and Hay, Front Neurosci., 2015, 9, pp 1-8), in rodent models of PD (Tanji et al., Biochem Biophys Res Commun., 2015, 465, pp746-752; He et al., Mol Neurobiol., 2015, DOI 10.1007/s12035-015-9173-7; Wu et al., Neuroscience, 2015, 284, pp 900-911).
There are several published papers showing the benefit of trehalose in animal models of PD when the trehalose is dissolved in the animal drinking water such that it is constantly available to the animals. These are summarized in Table 1 below.
TABLE 1TrehaloseModeladministeredEffectReferenceMPTP-2% trehalose inNeuroprotectionSarkar et al.,lesioneddrinking waterobservedNeurotoxicology, 2014,mouse44, 250-262.Rotenone-2% trehalose inNeuroprotectionWu et al.,lesioned ratdrinking waterobservedNeuroscience, 2015,284, pp 900-911AAV 2 and 5% inNeuroprotectionHe et al., Molα-synuclein drinking waterobservedNeurobiol., 2015, DOIrat10.1007/s12035-015-9173-7.Chronic1% in theNo behaviouralFerguson et al., BehavMPTP-drinking watereffect. SomeBrain Res., 2015, 292,lesionedeffect onpp 68-78.mousedopamine levelsTransgenic 2% trehalose inIncreasedTanji et al., Biochemα-synucleindrinking waterautophagyBiophys Res Commun.,mouse2015, 465, pp746-752.
These studies demonstrate the potential of trehalose as a treatment for PD. However, the most efficacious method of administering trehalose is unknown and uninvestigated with trehalose administered in the drinking water in all these studies. Similarly, whilst there are several papers in the literature showing a positive effect of trehalose in animal models of other neurodegenerative proteinopathies (e.g. Alzheimer's disease, amyotrophic lateral sclerosis and Huntington's disease) trehalose was administered in the drinking water.
Canadian Patent No. CA2608198 A1 (Lindquist et al., 2006) discloses a method of inhibiting α-synuclein-mediated cellular toxicity by contacting a cell expressing a toxicity-inducing amount or form of α-synuclein with an effective amount of an osmolyte, in which the osmolyte is trehalose.
As noted above, in all the previous work performed in animal models of PD, trehalose has been administered to animals as a solution in their drinking water. Furthermore, no fully quantitative methods have been used to measure trehalose levels in either the plasma or brain in these studies.
Determining the best dosage regime and methodology for delivery of the trehalose to give the most efficacious treatment of neurological disorders would be very beneficial. With a rapidly aging population, and with the cost of health care treatment increasing rapidly as a result, finding an economical and simple method of treating a wide variety of neurological disorders, including PD, would be very advantageous.